Methanesulfonamidophenyl guanidine compounds

ABSTRACT

Novel aromatic guanidine compounds found to have biological activity having the formula:   WHEREIN: R1 is hydrogen; R2 is methanesulfonamido; R3 is hydrogen or hydroxy; R4 is hydrogen; and R5 is hydrogen. The guanidine compounds and their salts are shown to be active as vasoconstrictor agents and create useful pharmaceutical preparations when deployed with a pharmaceutically acceptable carrier for administration to a host, e.g., man, requiring vasoconstrictive therapy.

United States Patent [1 1 Hughes et al.

Sept. 2, 1975 METHANESULFONAMIDOPHENYL GUANIDINE COMPOUNDS [75] Inventors: John Lawrence Hughes; Robert Chung-Huan Liu, both of Kankakee, Ill.

[73] Assignee: Armour Pharmaceutical Company,

Phoenix, Ariz.

[22] Filed: Apr. 15, 1974 21 App], No.: 460,816

Related U.S. Application Data [62] Division of Ser. No. 73.244, Sept. 17, 1970,

abandoned.

[52] U.S. Cl 260/556 A; 260/556 R; 424/321; 424/326 [5 1] Int. Cl. C07c 143/74; C07c 143/84 [58] Field of Search 260/556 A, 556 R [56] References Cited UNITED STATES PATENTS 2,359,363 10/1944 Kaiser 260/556 A 2.663.732 12/1953 Wcissherger 260/556 A Primary Examiner-Arthur P. Derners Attorney, Agent, or Firm-Richard R. Mybeck 5 7 ABSTRACT Novel aromatic guanidine compounds found to have biological activity having the formula:

NH II R 4 NHCNHR wherein: R is hydrogen; R is methanesulfonamido; R is hydrogen or hydroxy; R is hydrogen; and R is hydrogen. The guanidine compounds and their salts are shown to be active as vasoconstrictor agents and create useful pharmaceutical preparations when deployed with a pharmaceutically acceptable carrier for administration to a host, e.g., man, requiring vasoconstrictive therapy.

3 Claims, No Drawings METHANESULFONAMIDOPHENYL GUANIDINE COMPOUNDS RELATED APPLICATION This application is a divisional from our eo-pending U.S. application Ser. No. 73,244 filed on Sept. 17, 1970 for Novel Compounds and Methods of Using Same, now abandoned.

DESCRIPTION OF INVENTION This invention relates to generally novel chemical compounds and methods of using them to realize the benefits of their novel biological properties and more particularly to a class of novel aromatic guanidine compounds and their corresponding non-toxic acid addition salts which possess vasoeonstrictor properties and hence are useful as vasoeonstrictor agents.

The class of compounds embraced with the present invention and for which this patent is sought are represented by the structural notation:

wherein: R, is hydrogen; R is methanesulfonamido; R is hydrogen or hydroxy; R is hydrogen; and R,-, is hydrogen. The non-toxic acid addition salts of the guanidine compounds are also biologically active. All of the aforesaid compounds and salts are active vasoconstrio tor agents.

Representative of compounds suitable for practice of this invention are: 3'-methanesulfonamidophenylguanidine; and 3-methanesulfonamido-4'-hydroxyphenylguanidine. Representative of the salts embodied in this invention are: the nitrates; hydrochlorides; 3'- acetylmaleates; citrates and sulfates of said compounds. such for example as: 3-mcthanesulfonamidophenylguanidine maleate; 4'-hydroxy-3'-methanesulfonamidophenylguanidine hydrochloride; and the like.

The term vasoeonstrictor agents," as used herein to define the utility of the new compounds of this invention, means those agents which are useful to effect the amelioration of congestive states of the eye and nose, and in treatment of shock and other hypotensive states.

Compounds known previously as vasoeonstrictor agents, and the basis of current commercial efforts by the pharmaceutical industry are methoxamine, ephedrine, epinephrine. oxymetazoline, phcnylephrine, levartenenol, naphazolinc and tuaminoheptane.

While these compounds have been successful in providing the desired vasoconstrictive action, they have also been the cause of severe adverse reactions such as cardiac arrhythmias and excessive elevation of blood pressure. Further, such compounds. when employed in topical formulations are known to cause stinging, burning, and the sensation of intense dryness.

The present invention is predicated upon the discovery of new aromatic guanidine compounds and their corresponding non-toxic acid addition salts shown above, which possess remarkably unexpected properties as vasoeonstrictor agents and obtain vasoconstric tor activity without any significant changes in the cardiac rate of the host to whom such agents are administered. Further, as will appear, the compounds of this invention may be administered by oral, parenteral and topical routes with but minimal effects on the cardiac rate of the host animal, including man.

Accordingly, one of the prime objects of the present invention is to provide new chemical compounds which are useful.

Another object of the present invention is to provide new compounds which have biological activity and are useful as vasoeonstrictor agents.

A further object of the present invention is to provide new aromatic guanidine compounds which, per se, and in the form of the corresponding non-toxic acid addition salts can be employed as vasoeonstrictor agents and are free from significant effects on the cardiac rate of the host to whom it is administered.

Still another object of the present invention is to provide new aromatic guanidine compounds and methods of using them which are useful pharmaceuticals in the treatment of hypotensive states, and as nasal and ocular decongestants.

These and still further objects as shall hereinafter appear are fulfilled by the present invention in a remarkably unobvious fashion as will be discerned from the following detailed description and examples of embodiments of this invention.

The aromatic guanidine compounds of the present invention can be prepared by any of several procedures, for example, the addition of hydrogen cyanamide to an aromatic amine (or its mineral acid addition salt); the reaction of a l-aryl-Z-methyl-Z- thiopseudourea hydroiodie with ammonia or an alkyl amine and the like.

The guanidines may be converted to their acid addition salts by reacting the guanidine with an appropriate mineral or organic acid such, for example. as hydro chloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodie acid, maleic acid, citric acid, acetic acid, tartaric acid, benzoic acid, propionic acid, carbonic acid, and like acids to form pharmaceutically acceptable salts in a well known manner which does not need to be belabored here.

One such procedure for preparing the guanidines comprises the mixture of the appropriate aromatic amine mineral acid addition salt (or the aromatic amine with one molar equivalent of the appropriate mineral acid), aqueous 50 percent cyanamide solution and ethyl alcohol which is then heated at reflux for 3 to 20 hours. For optimum yield the molar ratio of arematic amine salt, cyanamide, and ethyl alcohol was l.():l.5:l5 respectively. The products, i.e., the aromatic guanidine mineral acid addition salts, are isolated from the reaction mixtures and purified by recrystalli zation from an appropriate solvent, i.e., water or aliphatic alcohols. When the acid addition salt could not be purified it was converted to the free base by the addition of an alkali hydroxide and purified by recrystallization from an appropriate solvent.

Another satisfactory method comprises forming a mixture of an appropriate laryl-2-methyl-2- thiopseudourea hydroiodide, an appropriate primary amine and ethyl alcohol. The mixture is heated at reflux for 20 hours. For optimum yield the molar ratio of the thiopseudourea, primary amine and ethyl alcohol was l:3:l5, respectively. The products are isolated from their reaction mixtures and converted to hydrochloride salts for purification and characterization.

A guanidine compound, prepared by either of the foregoing procedures, or by other suitable procedures, may be converted to its acid addition salt, e.g., hydrochloride by the addition of the appropriate acid to the guanidine compound.

The guanidine compounds of this invention may be employed as free bases or in the form of their non-toxic pharmaceutically acceptable salts. Thus, for example, organic and inorganic acid addition salts may be employed, such as the salts of hydrochloric, sulfuric. nitric, phosphoric, citric, acetic, lactic, tartaric, sulfamic, succinic, fumaric, maleic, ethanedisulfonic, hydrobromic, benzoic and similar non-toxic acids. The salts may be prepared by reacting the guanidine base with an excess of acid in a suitable solvent, such as ethanol, ac etone, water, or mixture thereof. The mixture is heated to effectsolution, and the salts crystallize on cooling.

The guanidines and their salts are administered in therapeutically effective amounts to animals, including man, and in appropriate ways. Thus, dosages of about 1 milligram to 5 milligrams per kilogram of host body weight, may be provided to man by systemic adminis tration, e.g., orally or parenterally. The compounds may be administered systemically to animals other than man in dosages of up to about 5 milligrams per kilogram of body weight. The foregoing and other dosage levels herein are based on the content of guanidine base. The compounds have excellent vasoconstriction, a low order of toxicity, and relatively few observed side effects.

In the preferred embodiments of the invention, an aromatic guanidine or a salt thereof is administered in a pharmaceutical composition which includes the guanidine compound and a pharmaceutical carrier. The carrier is a non-toxic pharmaceutical grade substance, which may be either solid or liquid. Suitable solid carriers include lactose, magnesium stearate, starch, sucrose, mannitol, sorbitol, cellulose powder, dicalcium phosphate, talc, stearic acid, gelatin, agar pectin, acacia and the like. Suitable liquid carriers include glycols, polyglycols, dimethylsulfoxide, peanut oil, olive I oil, sesame oil, alcohols, water, and the like. If desired, the carrier may include a time delay material such as glycerol mono-stearate, or glycerol di-stearate, alone or with a wax.

The composition preferably is provided in unit dosage form for accuracy and convenience in administration. Where appropriate, oral administration is effective and preferred, and dosage units suitable for oral administration are provided. Examples of such dosage units employing solid carriers include tablets, filled capsules, packets and the like, and lozenges. The amount of solid carrier per dosage unit may vary widely. preferably from about 25 milligrams to 5 gram.

The guanidines and their salts may be compounded with semi-solid and liquid carriers in solutions, suspensions, emulsions, ointments, suppositories and soft gelatin capsules, for example. Such compositions may be administered pancavally, i.e.. via natural and artificial openings in the body, such as the mouth, the anus, the vagina. the nares, and the stoma of colostomy patients. intravenously or intramuscularly, employing the appropriate composition having a suitable concentration of active ingredient according to the desired route of administration.

The foregoing dosage forms are prepared by conventional procedures of mixing, granulating, compressing, suspending and/or dissolving, as is suitable to prepare the desired dosage form.

The vasoconstriction of a host animal including man which has a condition requiring such treatment is readily obtained by administering to the afflicted host an aromatic guanidine or a pharmaceutically acceptable acid addition salt thereof in an amount sufficient to alleviate the symptoms of the condition. The usual symptoms requiring treatment are low blood pressure, ocular and nasal congestion, and the like.

The compound preferably is administered at the dosage level described above and preferably in a pharmaceutical carrier. The dosage level and frequency of administration are to a certain extent subjective, attention being given to the degree of vasoconstriction or decongestion, the case history, the reaction of the subject, and the like.

The daily dosage can be administered in one or more parts and the administration can be accomplished pancavally or parenterally or topically. Administration for the provision of systemic vasoconstriction is preferably oral and is most conveniently accomplished by means of a tablet containing one of the active compounds and a pharmaceutical carrier. For local vasoconstriction, that is, eyes, nose, etc., topical administration is preferred.

We have obtained especially good results when administering to the animal organism the following aromatic guanidines to obtain vasoconstriction therein. The guanidines so used are: 3-methanesulfonamidophenylguanidine; 3-methanesulfonamido-4'-hydroxyphenylguanidine; 3'-methanesulfonamidophenylguanidine maleate; and 4-hydroxy-3 methanesulfonamidophenylguanidine hydrochloride.

The onset of activity after oral administration in the animal organism is rapid, results being observed within /2 hour, and the activity is sustained. Thus, the activity levels remain high for 2 or more hours, and activity persists over a 24-hour period. After topical or intravenous administration the onset of action is rapid and persists for l or more hours.

Of the aromatic guanidines which may be employed to produce vasoconstriction or decongestion, those having meta and/or para substitution appear to provide most desirable results.

The following examples are illustrative of the preparation of the novel guanidines of the invention, new pharmaceutical compositions embodying said guanidines and their non-toxic acid addition salts, the treatment of the animal organism in accordance with the invention, and the activities exhibited in such treatment. It is to be understood that the invention is not limited to the examples or to the compounds, compositions, proportions. conditions, and methods set forth therein, which are only illustrative. Throughout the examples, the specific guanidines enumerated have been used to typify the entire class of compounds and compositions of the invention.

EXAMPLE I 3'-Methanesulfonamidophenylguanidine was prepared from a mixture of 22.3 g (().l mole) of 3- aminomethanesulfonanilide hydrochloride, l2.6 g of a 50 percent aqueous cyanamide solution (equivalent to 0.15 mole for cyanamide) and 100 ml of ethyl alcohol. The mixture was heated at reflux'temperature for 20 hours. The solvent was then evaporated and the residue was dissolved in water to which 8.4 g (0.1 mole) of sodium bicarbonate was added. The mixture was cooled for 5 hoursat C. The precipitated solid was collected on a filter and purified by recrystallization from water. The white crystalline solid melted at 24I-3C (dec.). The infrared spectrum was consistent with the assigned structure.

Analysis: Caled. for C H N O S: C, 42.09; H. 5.30; N 24.55;

S. 1404. Found: C, 42.35; H, 5.53; N. 24.53;

EXAMPLE II 4 -Hydroxy-3 -methanesulfonamidophenylguanidine hydrochloride was prepared using the reaction procedure of Example 1 except that 5-amino-2-hydroxymethanesulfonanilide hydrochloride was used in place of the 3-aminomethanesulfonanilide hydrochloride. The reaction mixture was cooled for 5 hours at 0C and the precipitated solid collected on a filter. The product was purified by recrystallization from water. The infrared spectrum was consistent with the assigned structure.

Analysis: Calcd. for C,.H,:,CIN,O:,S: C, 34.22; H, 4.68; CI, l2.63;

N, 19.96; S, I L42. Found: C, 3415; H, 4.77; CI, I180;

N, 20.03; S. ll.32.

EXAMPLE III The following are examples of several dosage forms useful for the practice of the present invention using oral administration.

FORMULATION A'- Magnesium Stearatc l 5 FORMULATION *D Ingredient Parts Guanidine Compound 60 300 Corn Starch 25 5O Lactose 25 200 Talc IO 5O Silica (powdered) O.l 2

FORMULATION E Ingredient Parts Guanidine Compound 60 30 Lactose I90 Cellulose l0 I35 Magnesium Stearate 0.I 5

FORMULATION F" Ingredient Parts Guanidine Compound 60 300 Cellulose l5 200 Corn Starch l0 50 Gelatin 5 35 Stearie Acid l5 FORMULATION G" Ingredient Parts Guanidine Compound 60 300 Tricalcium Phosphate 50 I50 Corn Starch l0 5O Acacia 5 25 Magnesium Stearate l 5 In each instance, the ingredients in the proportions indicated are milled to a uniform powder, sized, mixed with binder and compressed into tablets.

EXAMPLE IV Suppositories melting at about 60F and each having the following composition are produced by compounding the ingredients in the relative proportions indicated and heating the ingredients to about 60F to effect a solution. The solution is then poured into cooled molds and allowed to cool and solidify.

Ingredient Amount Guanidinc Compound O.I to 1.0 mg

Base of lactose, polyethylene glycol, polyethylene glycol 400. polyethylene glycol 4000, polysorhate and glycerine I gram EXAMPLE V A glosset for sublingual administration was prepared using 60 to 300 mg of guanidine compound disposed in a rapidly disintegrating base formed of starch, lactose, sodium saccharin and talcum.

EXAMPLE VI The ingredients of the following compositions were compounded to provide a solution suitable for intravenous administration. In each instance, the ingredients were mixed and warmed to about 5060C with stirring to effect solution. The solution was then sterile filtered, cooled to room temperature, and packaged in sterile vials.

FORMULATION H 5 catheter connected to a pressure transducer. host heart Guunidinc Compound m 500 mg rate was determined from the limb electrocardiogram, Sodium Chloride 890 mg and caitoid arterial blood flow was continuously moni- Water 99 g FORMULATION tored with a flow probe around the artery which probe was connected to an electromagnetic flow meter. It will lngrcdcm Ammm I be noted that three standard vasoconstrictors, all cur- Guanidinc Compound 500 mg rent commercial products, were also assayed in this Glucose 5 g manner and provide a reference base. The test comt 95 g pounds are coded in Table I and the data is reported in subsequent tables below.

TABLE 1 EXAMPLE VII The ingredients of the following compositions were Test cumpound compounded to provide a solution suitable for intracmlc Chemical Name muscular and subcutaneous formulations administra- G 3. Mcthuncsulfonamidophcnyl guunidinc tion. In each instance, the ingredients were mixed and M 3-Methanesulfoiiamido-4-hydroxyphenyl warmed to about 5060C with stirring to effect soluguim'dmc hydmchmrdc tion. The solution was then sterile filtered, cooled to TABLE room temperature, and packaged in sterile vials. Heart R h ng in Ane thetized Dogs Dose (mg/Kg.i.v.) Test Compound 0.01 ().I l.()

G 7.. FORMULATION .I M

Naphazoline Ingredient Amount ph l h i Phcnylpro- Guanidine Compound l() 500 mg pdnoluminc i I671 Aqueous Gelatin Containing 0.5% Ruling Scnle' Phenol 100 g W Dem-Sc In heart run:

FORMULATION K 1) No change in heart rate lngrcdicnt Amount Increase in heart rate Guanidine Compound 10 500 mg Sodium Chloride 890 g EXAMPLE X Water 99 g FORMULATION Additional data was obtained for each representative I compound by measuring the rise in mean arterial blood Ingredient Amount 4U pressure after intravenous administration to an anes- Guanidine Compound III 500 mg thCtIZOd dog.

i The scale employed to evaluate the results is shown FORMULATION M" in Table III, and the test data is recorded in Table IV, using the code for test compounds set forth in Table I Ingredient Amount of Example IX. Guanidine Compound I() 500 mg 10-907: Aqueous TABLE Polyethylene 100 (Nicol 400 g Activity Pressure Rise Rating in mm Hg o 0 3 EXAMPLE VIII I 4 l0 2 ll 15 The guanidine compound is dispersed in a cream ve- 3 3 o hicle consisting of a water-miscible base of stearic acid, 2 Z propylene glycol, sorbitol monostearate and mono s5 oleate, polyoxyethylene sorbitan monostearate with citric acid and methyl and propyl parabens prescrva- T BLE Iv tivcs. Concentration of the guanidinc compound is 0.1 A to 50 mg per gram of vehicle.

Alternately the guanidine co pound may be dis- Ruling g 213121 CC r persed in corn oil, sesame oil C( tton seed oil, peanut Test Compound on. (LI in oil, or polyethylene glycols with the addition of appro- V (I priate preservatives. 2 i Naphaloline 3 4 4 bXAMPL]: IX Phenylcphrine 3 5 5 i g t (I Phenylpro- The vasoeonstrictor properties ot several representapmmkumm U 1 5 tive compounds of this invention were determined pharinaeologically using accepted methodology. The

heart rate changes in anesthetized dogs who received an intravenous dosage of a guanidine compound as indicated. Throughout the procedure, host blood pressure was monitored by means of an indwelling arterial EXAMPLE x1 FORMULATION N Ingredient Wtfl:

Guanidine Compound 2.00 Monh' sodium phosphate ().l() Dihasic Sodium phosphate 0.12 Sodium bisulfite 0.20 Sodium chloride 0.15 Mcrthiolate sodium (Thimcrosal) (Hll Water 97.42

From the foregoing. it becomes apparent that the invention herein described and illustrated fulfills all of our objectives. express and implied, in a remarkably unexpected fashion and that we have developed new and useful compounds, pharmaceutical compositions and therapeutic methods for providing vasoconstriction in hosts requiring such therapy.

What is claimed is:

l. Aromatic guanidine compounds having the formula NH ll NHCNHIR wherein: R is hydrogen; R is methanesulfonamido; R is hydrogen or hydroxy; R is hydrogen; and R is hydrogen.

2. A compound according to claim 1 denominated 3 methanesulfonamidophenyl guanidine.

3. A compound accordingto claim 1 denominated 3 -methanesulfonamido-4 -hydroxyphenylguanidine. 

1. AROMATIC GUANIDINE COMPOUNDS HAVING THE FORMULA
 2. A compound according to claim 1 denominated 3'', methanesulfonamidophenyl guanidine.
 3. A compound according to claim 1 denominated 3''-methanesulfonamido-4''-hydroxyphenylguanidine. 